1) Immune checkpoint inhibitors: Immune checkpoint inhibitors have changed the landscape for management of cancer. The greatest success has been in T-cell immune checkpoint inhibitors that improved outcomes in patients who are refractory to chemotherapy. In non-Hodkin lymphoma, the success of T-cell immune checkpoint inhibitors has been limited and further patient enhancement strategies are needed. Rare lymphomas including those that involve EBV or those in the CNS may benefit from T-cell immune checkpoint inhibitors of the PD-1 pathway. Other immune checkpoint inhibitors are also in development, including those which are designed to activate macrophages. A novel monoclonal antibody, Hu5F9, has undergone clinical testing and has good clinical activity in subsets of patients with both diffuse large B-cell lymphoma and indolent lymphomas. We aim to expand our understanding of which patients benefit from immune checkpoint inhibitors and better elucidate their mechanisms of action. In a series of clinical trials, we are testing the clinical efficacy of immune checkpoint inhibitors as either monotherapy in rare tumor types or as combination therapy in more common B-cell lymphomas. With a strong emphasis on translational endpoints, our goal is to identify safe regimens and better predict who is likeliest to benefit from these novel therapies. 2)PI3K inhibitors: This study will evaluate the safety and efficacy of copanlisib and rituximab when used as frontline induction therapy for patients with untreated FL. Patients who achieve CR after the initial 6 induction cycles of copanlisib and rituximab will be allowed to stop therapy and will undergo active surveillance for relapse with periodic CT scans and assays for ctDNA. Patients who achieve a PR after the initial 6 induction cycles of copanlisib and rituximab will be treated with an additional 6 cycles of extended induction therapy before stopping therapy and initiating active surveillance. Patients who do not achieve at least a PR after the initial 6 induction cycles of copanlisib and rituximab will stop therapy and initiate active surveillance. All patients who relapse or progress after copanlisib and rituximab induction therapy and meet clinical criteria for salvage therapy will be offered standard treatment with a monoclonal anti-CD20 antibody and chemotherapy. An important objective of this study is to determine the molecular correlates of response to copanlisib. 3) BTK inhibitors: Our NCI Lymphoma group identified bruton's tyrosine kinase (BTK) as a therapeutic target in diffuse large B-cell lymphoma. Phase 2 clinical trial of ibrutinib led to an understanding of the molecular underpinnings of response to BTK and a phase 3 study was performed in DLBCL adding BTK inhibitors to standard chemotherapy. Although the trial did not show a significant difference in clinical outcomes, subsets of patients had improvements in overall survival. Other aggressive B-cell lymphomas also respond to BTK inhibitors, including those involving the central nervous system (CNS). Both primary CNS lymphoma (PCNSL) and secondary CNS lymphomas (sCNSL) respond to ibrutinib. We are adding BTK inhibitors (both acalabrutinib and ibrutinib) to chemotherapy backbones in DLBCL, PCNSL, and SCNSL with a goal of improving the cure rate of these lymphomas.